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Efficacy and Safety of Oral Conivaptan: A V_1A/V₂ Vasopressin Receptor Antagonist, Assessed in a Randomized, Placebo-Controlled Trial in Patients with Euvolemic or Hypervolemic Hyponatremia

Division of Cardiology, Wayne State University (J.K.G.), Detroit, Michigan 48201; Jacksonville Center for Clinical Research (M.J.K.), Jacksonville, Florida 32216; Pulmonary Consultants (J.R.T.), Tacoma, Washington 98405; Cato Research (E.B.-A., K.F., W.A.L.), Durham, North Carolina 27713; and Astellas Pharma U.S. (N.S.), Inc., Deerfield, Illinois 60015

Address all correspondence and requests for reprints to: Dr. Jalal K. Ghali, Division of Cardiology, Wayne State University, 4201 St. Antoine, Detroit, Michigan 48201. E-mail: jghali{at}med.wayne.edu.

Context: Hyponatremia [serum sodium concentration ([Na⁺]), <135 mEq/liter] is the most common fluid and electrolyte abnormality among hospitalized patients. It is frequently caused by the inappropriate release of arginine vasopressin.

Objective: The objective of this study was to evaluate the efficacy and safety of oral conivaptan, a vasopressin V_1A/V₂ receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia.

Design: The study design was a 5-d placebo-controlled, randomized, double-blind study.

Setting: The study was performed at a hospital.

Intervention: Oral conivaptan (40 or 80 mg/d) or placebo was given in two divided doses.

Patients: Seventy-four patients (average baseline serum [Na⁺], 115 to <130 mEq/liter) were studied.

Main Outcome Measure: The main outcome measure was the change from baseline in serum [Na⁺] area under the curve.

Results: The least-squares mean change from baseline in the serum [Na⁺] area under the curve with conivaptan (40 and 80 mg/d) was 2.0-fold (P = 0.03) and 2.5-fold (P < 0.001) greater, respectively, than that with placebo. The median time to achieve a confirmed increase in serum [Na⁺] of 4 mEq/liter or more from baseline was 71.7 h for placebo, 27.5 h for 40 mg/d conivaptan (P = 0.044), and 12.1 h for 80 mg/d conivaptan (P = 0.002). The mean total times during which patients had a serum [Na⁺] level of 4 mEq/liter or more above baseline were 46.5, 69.8, and 88.8 h (P = 0.001), respectively. The least-squares mean change in serum [Na⁺] from baseline to end of treatment was 3.4 mEq/liter for placebo, 6.4 mEq/liter for 40 mg/d conivaptan, and 8.2 mEq/liter for 80 mg/d conivaptan (P = 0.002). A confirmed normal serum [Na⁺] (135 mEq/liter) or increase of 6 mEq/liter or more was observed in 48% of patients given placebo, 71% given 40 mg/d conivaptan, and 82% given 80 mg/d conivaptan (P = 0.014). Headache, hypotension, nausea, constipation, and postural hypotension were the most common adverse events.

Conclusion: Oral conivaptan (40 and 80 mg/d) was well tolerated and efficacious in correcting serum [Na⁺] in hyponatremia.

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